Endocrine Abstracts

At least 90% of human ovarian cancers may originate in the OSE. Most studies indicate that EOC is oestrogen responsive. Paradoxically, ovarian cancer generally occurs after the menopause, so the question arises if oestrogen is involved, where does it come from? We hypothesise that the high circulating concentrations of conjugated (inactive) oestrogens in post-menopausal women are substrates for formation of active oestrogen in the OSE through the hydrolytic enzyme activity of STS. We previously showed that STS is expressed in normal OSE and EOC and that SKOV-3 cells respond to IL-1α with a 2-fold increase in STS mRNA. We now investigate STS enzymic activity and also 17 βHSD5 presence and regulation in EOC, OSE and ovarian cancer cell lines.

Normal ovaries and ovarian tumours were collected with consent and local Ethical Committee approval from women undergoing surgical procedures. 17 βHSD5 was detected in paraffin-embedded tissue sections using a mouse monoclonal antibody against human 17 βHSD5. SKOV-3 cancer cell lines were cultured in the presence or absence of inflammatory cytokines and 17β oestradiol (E₂) or IL-1 receptor antagonist (ILRA). mRNA was extracted and transcribed cDNA was analysed for expression of STS and 17 βHSD5 gene expression using pre-validated reagents for Q-RTPCR. TLC was performed to measure [³H]-oestrone(E₁) sulphate conversion to [³H]-E₁and [³H]-E₂, reflecting STS and 17 βHSD5 activity respectively.

Immunohistochemistry confirmed the presence of 17 βHSD5 protein in normal OSE and EOC. In SKOV-3 cells IL-1α was the most stimulatory cytokine and enhanced STS mRNA expression and activity 2-fold in a time dependent manner. ILRA inhibited IL-1α stimulation in STS mRNA. SKOV-3 cells responded to IL-1α with a 2-fold increase in 17 βHSD5 mRNA.

These results confirm STS and 17 βHSD5 expression in normal OSE and EOC and that SKOV-3 cells respond to inflammatory cytokines with an increase in STS mRNA and activity. We therefore see evidence for a mechanism whereby circulating conjugated oestrogens could be converted locally to active oestrogen in normal OSE in post-menopausal women, and in EOC.